Medical science has long recognized the desirability of prolonging the time during which a drug is pharmacologically active. A significant advantage is to decrease the frequency with which the patient has to take the drug or be given the drug. This is particularly important when patient compliance problems are encountered such as with psychiatric patients or with the senile. Extending the pharmacological activity of the drug can have significant therapeutic benefits, for example, by permitting a patient to sleep undisturbed throughout the night. Perhaps most significantly, the patient is exposed to less total active drug during any given period of time, minimizing or eliminating local and systemic side effects. Prolonged action drug formulations have utility in veterinary medicine, particularly in the treatment of free-ranging animals.
A variety of methods have been devised in an attempt to increase drug release time, including oral, parenteral and topical application techniques. For example, drugs have been encapsulated in polymer or in slowly-dissolving coating material, or have been dispersed in an insoluble or slowly-dissolving matrix. Prolonged activity formulations designed for subcutaneous and intramuscular injection have been prepared by using polymers to complex or absorb the drug molecules in solution. Other techniques include suspension of polymer particles into which the drug is dispersed, suspension of microcapsules of the drug, use of solutions or suspensions of the drug in oil, or emulsions with oil, and implanting various slow release devices or pellets. These and other methods for providing prolonged activity are described in "Sustained and Controlled Release Drug Delivery Systems" by J. R. Robinson, Marcel Dekker, Inc., New York, 1978 (Volume 6 of "Drugs and the Pharmaceutical Sciences" Series, edited by J. Swarbrick).
Most pertinent to the present development are the methods described by Anthony A. Sinkula in Chapter 6 of the foregoing text relating to the chemical approach to sustained drug delivery; that Chapter 6 is incorporated herein by reference. Such methods are based upon localization of the drug in a biological depot or site within the organism with slow release to provide the active form of the drug over an extended length of time. The author describes preparation of chemical derivatives of a wide variety of drugs to increase the sustained release property of the drug molecule. In many cases, the parent molecule is regenerated in vivo by a hydrolytic mechanism. While the chemical approach would seem to offer hope for a wide variety of custom tailored prolonged action drugs, when the derivative is formulated so as to provide a significant level of drug delivery, there are a number of drawbacks pointed out by Sinkula. For example, the resulting changes in the physiochemical properties of the modified drug may well produce pharmacological and biochemical changes different from those found in the parent drug molecule. The predictability of these changes is difficult to assess, and frequently it is not possible to alter only one property of the drug. It will be appreciated that the foregoing problems arise as a result of attempting to provide a modified drug at a concentration level having substantial pharmacological activity.
The present invention provides a prolonged action drug formulation in which chemical derivatives of the desired drug are utilized, for example, as a matrix or coating within which the desired drug is located. However, in the present invention as compared to the prior use of drug derivatives, the concentration of the drug derivatives are such as to provide only minor pharmacological activity. Rather than simply relying upon regeneration of the drug by decomposition of a derivative, according to the present invention the derivatives retain their identity for an extended period of time in combination with desired quantities of the drug itself, serving by such combination to impede the release of the drug. Succinctly, the desired drug is dispersed in at least one suitable chemical derivative which has a reduced aqueous solubility and reduced dissolution rate.
It will be appreciated that there are several advantages to the present invention. In particular, since the pharmacological activity of the modified drug is minor relative to the activity of the drug with which it is in combination, there is little likelihood of pharmacological and biochemical changes in the derivative; there is thus a cost savings through reduced toxicity testing and dosage development time. The relationship between drug release and concentration in the combination can be readily determined and customized for any particular application by simple changes in concentration and/or the manner by which the drug and derivative are placed in combination. For example, it may be desirable to include free drug and combined drug-derivative particles in a particular formulation. In contrast to some prior art vehicles which are not biodegradable, the derivatives will eventually break down and be removed undergoing a reaction such as hydrolysis to reform the original drug.
More particularly, the prolonged action drug formulation of the present invention comprises a pharmacologically effective amount of a drug in solid form dispersed in or coated by at least one solid chemical derivative of the drug which has minor pharmacological activity relative to the drug, in a concentration which is sufficient to substantially prolong the time during which the drug is released and is pharmacologically active. The combination is preferably a substantially intimate and uniform mixture, for example obtained by physical admixture followed by compaction and comminution, or by coprecipitation from a common solution, or the drug and derivative can be melted together to form a fused solid; in a preferred procedure, the derivative or derivatives are coated onto, or otherwise encapsulate, particles of the drug. In this regard, one or more derivatives can be formed at the surface of the drug particles by chemical reactions as hereinafter described. The combination has particular usefulness when administered subcutaneously or intramuscularly.
The aqueous solubility (in pH 7 phosphate buffered solution) of the derivative should be less than 0.20 mg./ml., preferably less than 0.01 mg./ml. Depending upon the particular derivative and parent drug, the drug will generally constitute about 25-95 weight percent of the combination.
The prior art has used a variety of terms to characterize long-acting formulations. While one could draw distinctions between phrases such as "sustained action", "controlled release", "delayed release" and the like, as a practical matter, these terms can be used somewhat interchangeably. In this specification, the term "prolonged action" will be used to indicate all long-acting formulations, that is, formulations that have pharmacokinetic characteristics such that the formulation provides an extended length of release time than is normally found for the released drug itself.